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Conference Paper: Vascular adaptive response in chronic liver hypoxia

TitleVascular adaptive response in chronic liver hypoxia
Authors
Issue Date2004
Citation
The 2004 Hong Kong-Shanghai International Liver Congress, Hong Kong, 14-17 February 2004. In Journal of Gastroenterology and Hepatology, 2004, v. 19 suppl. S2, p. A85, abstract no. ABS00102 How to Cite?
AbstractINTRODUCTION: Cardiovascular adaptation is well recognized in the form of vascular remodeling in the lungs and hypertrophy of the heart that are necessary for relieving the state of hypoxemia. In chronic lung hypoxia, there is a shift in the production metabolites away from vasodilators to vasoconstrictors. The vascular response for adaptation in chronic liver hypoxia is poorly understood. Furthermore, prolonged hypoxia is a common underlying event in most chronic liver diseases such as alcoholic liver disease, cirrhosis and malignancy. Studying the events related to the gene expression in the liver during hypoxia could lead to a better understanding on how to modulate new treatment approaches in the management of liver diseases in which hypoxia is a major factor. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate the adaptive response to hypoxia. These genes include erythropoietin, VEGF and glycolytic enzymes. In the present study, we determined the hepatic expression of hypoxia-inducible factor 1 (HIF-1) in hypoxia as well as the expression of downstream genes that carry the hypoxic response element (HRE) such as iNOS, VEGF and ET-1. These genes modulate the vascular response through nitric oxide. We also evaluated the role of other nuclear transcription factors such as nuclear factor kappa B (NF-kB) and activator protein–1 (AP-1). eNOS is regulated by AP-1. MATERIALS AND METHODS: Blood and liver samples from adult SD rats were collected at various time-points. Samples from normoxic and hypoxic rats were analyzed for different genes and proteins using histological analysis, immunohistochemistry, serum ALT, hematocrit, lipid peroxidation (8-isoprostane), RT-PCR, Western Blotting and EMSA. RESULTS: Our results showed that there was a significant increase in the hematocrit levels from day 7 to day 28 in the hypoxic rats when compared with normoxic controls. A significant weight loss was also observed from day 7 to day 28 in the hypoxic group. Right ventricular hypertrophy occurred in hypoxic rats. The liver morphology and serum ALT were within normal range at all time-points suggesting the absence of significant necroinflammation. Also, 8-isoprostane levels were not elevated in either group at all time-points. iNOS mRNA peaked in hypoxic liver at day 21 and then decreased by day 28 but was higher than normoxic controls. Nitrotyrosine protein levels were not significantly increased at any of the time-points. eNOS, VEGF and ET-1 mRNAs progressively increased from day 7 to day 28 in hypoxic liver when compared with normoxic controls. The trends observed at the transcription level were confirmed at the protein level as determined by Western blot analysis. HIF-1a, NK-kB and AP-1 were upregulated in hypoxic liver when compared to the normoxic control. Our data suggest that the vascular adaptive ability of the liver in a prolonged state of oxygen deprivation triggers compensatory mechanisms for survival towards a vasodilatory response by expressing significant levels of nitric oxide through HIF-1a, NK-kB, AP-1, HRE and eNOS genes. There was no significant necroinflammatory change or increased oxidative stress in the hypoxic liver.
DescriptionFree Paper Abstracts
Persistent Identifierhttp://hdl.handle.net/10722/95347

 

DC FieldValueLanguage
dc.contributor.authorTipoe, GLen_HK
dc.contributor.authorLau, YHen_HK
dc.contributor.authorFung, MLen_HK
dc.contributor.authorLiong, Een_HK
dc.contributor.authorNanji, AAen_HK
dc.date.accessioned2010-09-25T15:59:19Z-
dc.date.available2010-09-25T15:59:19Z-
dc.date.issued2004en_HK
dc.identifier.citationThe 2004 Hong Kong-Shanghai International Liver Congress, Hong Kong, 14-17 February 2004. In Journal of Gastroenterology and Hepatology, 2004, v. 19 suppl. S2, p. A85, abstract no. ABS00102en_HK
dc.identifier.urihttp://hdl.handle.net/10722/95347-
dc.descriptionFree Paper Abstracts-
dc.description.abstractINTRODUCTION: Cardiovascular adaptation is well recognized in the form of vascular remodeling in the lungs and hypertrophy of the heart that are necessary for relieving the state of hypoxemia. In chronic lung hypoxia, there is a shift in the production metabolites away from vasodilators to vasoconstrictors. The vascular response for adaptation in chronic liver hypoxia is poorly understood. Furthermore, prolonged hypoxia is a common underlying event in most chronic liver diseases such as alcoholic liver disease, cirrhosis and malignancy. Studying the events related to the gene expression in the liver during hypoxia could lead to a better understanding on how to modulate new treatment approaches in the management of liver diseases in which hypoxia is a major factor. Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding proteins that mediate the adaptive response to hypoxia. These genes include erythropoietin, VEGF and glycolytic enzymes. In the present study, we determined the hepatic expression of hypoxia-inducible factor 1 (HIF-1) in hypoxia as well as the expression of downstream genes that carry the hypoxic response element (HRE) such as iNOS, VEGF and ET-1. These genes modulate the vascular response through nitric oxide. We also evaluated the role of other nuclear transcription factors such as nuclear factor kappa B (NF-kB) and activator protein–1 (AP-1). eNOS is regulated by AP-1. MATERIALS AND METHODS: Blood and liver samples from adult SD rats were collected at various time-points. Samples from normoxic and hypoxic rats were analyzed for different genes and proteins using histological analysis, immunohistochemistry, serum ALT, hematocrit, lipid peroxidation (8-isoprostane), RT-PCR, Western Blotting and EMSA. RESULTS: Our results showed that there was a significant increase in the hematocrit levels from day 7 to day 28 in the hypoxic rats when compared with normoxic controls. A significant weight loss was also observed from day 7 to day 28 in the hypoxic group. Right ventricular hypertrophy occurred in hypoxic rats. The liver morphology and serum ALT were within normal range at all time-points suggesting the absence of significant necroinflammation. Also, 8-isoprostane levels were not elevated in either group at all time-points. iNOS mRNA peaked in hypoxic liver at day 21 and then decreased by day 28 but was higher than normoxic controls. Nitrotyrosine protein levels were not significantly increased at any of the time-points. eNOS, VEGF and ET-1 mRNAs progressively increased from day 7 to day 28 in hypoxic liver when compared with normoxic controls. The trends observed at the transcription level were confirmed at the protein level as determined by Western blot analysis. HIF-1a, NK-kB and AP-1 were upregulated in hypoxic liver when compared to the normoxic control. Our data suggest that the vascular adaptive ability of the liver in a prolonged state of oxygen deprivation triggers compensatory mechanisms for survival towards a vasodilatory response by expressing significant levels of nitric oxide through HIF-1a, NK-kB, AP-1, HRE and eNOS genes. There was no significant necroinflammatory change or increased oxidative stress in the hypoxic liver.-
dc.languageengen_HK
dc.relation.ispartofJournal of Gastroenterology and Hepatologyen_HK
dc.titleVascular adaptive response in chronic liver hypoxiaen_HK
dc.typeConference_Paperen_HK
dc.identifier.emailTipoe, GL: tgeorge@hkucc.hku.hken_HK
dc.identifier.emailFung, ML: fungml@hkucc.hku.hken_HK
dc.identifier.authorityTipoe, GL=rp00371en_HK
dc.identifier.authorityFung, ML=rp00433en_HK
dc.description.natureLink_to_subscribed_fulltext-
dc.identifier.doi10.1111/j.1440-1746.2004.abs_2.x-
dc.identifier.pmid15185674-
dc.identifier.hkuros88113en_HK
dc.identifier.volume19en_HK
dc.identifier.issuesuppl. S2-
dc.identifier.spageA85, abstract no. ABS00102en_HK
dc.identifier.epageA85, abstract no. ABS00102-

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